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Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib

John C. Byrd, Richard R. Furman, Steven E. Coutre, Jan A. Burger, Kristie A. Blum, Morton Coleman, William G. Wierda, Jeffrey A. Jones, Weiqiang Zhao, Nyla A. Heerema, Amy J. Johnson, Yun Shaw, Elizabeth Bilotti, Cathy Zhou, Danelle F. James and Susan O'Brien

Data supplements

Article Figures & Data

Figures

  • Figure 1

    Serial assessment of adverse events over time. (A) Grade ≥3 AEs by time to event onset from first dose date. The dashed line denotes a 5% rate; x-axis maximum is 50%. (B) Frequency of grade ≥3 AEs by TN or R/R status.

  • Figure 2

    Response to ibrutinib over time. (A) Median percent change from baseline in the ALC and the sum of the products of lymph node diameters (SPD) in all patients, showing 95% confidence intervals for all patients. (B) Curves for cumulative best response (CR, PR, and PR-L) for all patients (N = 132). Results for TN patients (n = 31) are shown in C and D. Results for R/R patients (n = 101) are shown in E and F.

  • Figure 3

    Hemoglobin levels and platelet counts in all treated patients with baseline anemias and thrombocytopenias, respectively.

  • Figure 4

    PFS. (A) Kaplan-Meier curves of PFS in TN and R/R patients. (B) Kaplan-Meier curves of PFS in patients with del(17p) or del(11q) or without del(17p) or del(11q). (C) Kaplan-Meier curves of PFS from day 365 in patients who achieved CR and PR or PR-L within the first 364 days on study.

  • Figure 5

    OS. (A) Kaplan-Meier curves of OS in TN and R/R patients. (B) Kaplan-Meier curves of OS in patients with del(17p) or del(11q) or without del(17p) or del(11q).

Tables

  • Table 1

    Patient characteristics at baseline

    TN ≥65 years (n = 31)R/R (n = 101)All patients (N = 132)
    Median age, years (range)71 (65-84)64 (37-82)68 (37-84)
     ≥70 y, n (%)23 (74)34 (34)57 (43)
    Sex, n (%)
     Male19 (61)79 (78)98 (74)
     Female12 (39)22 (22)34 (26)
    ECOG PS, n (%)
     023 (74)43 (43)66 (50)
     18 (26)54 (53)62 (47)
     20 (0)4 (4)4 (3)
    Bulky disease, n (%)
     ≥5 cm6 (19)55 (54)61 (46)
     ≥10 cm015 (15)15 (11)
    Baseline Rai stage, n (%)
     0-II13 (42)38 (38)51 (39)
     III-IV17 (55)58 (57)75 (57)
     Unknown1 (3)5 (5)6 (5)
    Cytogenetics/FISH, n (%)
     Del(17p)2 (6)34 (34)36 (27)
     Del(11q)1 (3)35 (35)36 (27)
     Trisomy 128 (26)12 (12)20 (15)
     Del(13q)17 (55)47 (47)64 (49)
     β2-microglobulin level >3 mg/L, n (%)8 (26)49 (49)57 (43)
     Unmutated IGHV, n (%)15 (48)79 (78)94 (71)
    Median ANC, × 109/L (range)3.9 (0-19.4)2.5 (0-19)2.6 (0-19.4)
     ANC ≤1.5 × 109/L1 (3)34 (34)35 (27)
    Median hemoglobin, g/L (range)122 (77-157)115 (62-176)117 (62-176)
     ≤11 g/dL, n (%)11 (35)42 (42)53 (40)
    Median platelets, × 109/L (range)113 (32-217)105 (2-310)105 (2-310)
     ≤100 × 109/L, n (%)12 (39)49 (49)61 (46)
    Hemoglobin ≤11 g/dL or platelets ≤100 × 109/L, n (%)20 (65)61 (60)81 (61)
    Median ALC, × 109/L (range)41.1 (0.3-240.2)8.9 (0.1-298.9)13 (0.1-299)
    Median CrCl, mL/min (range)67 (31-156)81 (36-213)79 (31-213)
     <60 mL/min, n (%)9 (29)20 (20)29 (22)
    Median prior therapy, n (range)4 (1-12)
    Number of prior therapies, n (%)
     1-227 (27)
     314 (14)
     ≥460 (59)
    Prior systemic therapy, n (%)
     Chemotherapy101 (100)
     Nucleoside analog97 (96)
     Alkylator (including bendamustine)92 (91)
     Any anti-CD20–based therapy99 (98)
     Anti-CD20–based chemoimmunotherapy97 (96)
     Anti-CD52–based therapy (alemtuzumab)23 (23)
     Idelalisib6 (6)
    • CrCl, creatinine clearance; FISH, fluorescence in situ hybridization.

  • Table 2

    Three-year safety of ibrutinib in patients with CLL and SLL

    TN ≥65 years (n = 31)R/R (n = 101)All patients (N = 132)
    Median treatment duration, months (range)30 (0.3-44)23 (0.3-45)25 (0.3-45)
    Treatment duration
     ≤1 years5 (16)24 (24)29 (22)
     >1-2 years1 (3)31 (31)32 (24)
     >2-3 years15 (48)33 (33)48 (36)
     >3 years10 (32)13 (13)23 (17)
    Grade ≥3 AEs
     Hematologic4 (13)32 (32)36 (27)
     Nonhematologic18 (58)83 (82)101 (77)
     Infections4 (13)52 (51)56 (42)
    Dose reductions
     ≤1 years1/31 (3)10/101 (10)11/132 (8)
     >1-2 years1/26 (4)0/77 (0)1/103 (1)
     >2-3 years0/25 (0)1/46 (2)1/71 (1)
     >3-4 years0/10 (0)0/13 (0)0/23 (0)
    Patients rolled over to long-term extension study (PCYC-1103)26 (84)69 (68)95 (72)
    Patients remaining on ibrutinib treatment25 (81)54 (53)79 (60)
    Primary reasons for discontinuation
     Disease progression1 (3)21 (21)22 (17)
     AE3 (10)12 (12)15 (11)
     Consent withdrawal2 (6)4 (4)6 (5)
     Investigator decision09 (9)*9 (7)
     Other01 (1)1 (1)
     Death on study1 (3)13 (13)14 (11)
    • Values are n (%) unless otherwise noted.

    • * Within 30 days of last dose.

    • Including 4 patients who went to stem cell transplant.

  • Table 3

    Grade ≥3 AEs with ≥3% incidence

    Adverse event*TN ≥65 years (n = 31)R/R (n = 101)Total (n = 132)
    Hypertension7 (23)20 (20)27 (20)
    Pneumonia2 (6)25 (25)27 (20)
    Neutropenia1 (3)18 (18)19 (14)
    Thrombocytopenia1 (3)10 (10)11 (8)
    Atrial fibrillation2 (6)6 (6)8 (6)
    Diarrhea5 (16)3 (3)8 (6)
    Fatigue1 (3)5 (5)7 (5)
    Sepsis07 (7)6 (5)
    Cellulitis05 (5)5 (4)
    Dehydration05 (5)5 (4)
    Febrile neutropenia05 (5)5 (4)
    Hyperglycemia1 (3)4 (4)5 (4)
    Hypokalemia1 (3)4 (4)5 (4)
    Sinusitis05 (5)5 (4)
    Bacteremia04 (4)4 (3)
    Decreased appetite04 (4)4 (3)
    Decreased lymphocyte count1 (3)3 (3)4 (3)
    Increased lymphocyte count04 (4)4 (3)
    Leukocytosis04 (4)4 (3)
    Lymphocytosis04 (4)4 (3)
    Syncope1 (3)3 (3)4 (3)
    • Values are n (%).

    • * AEs are listed by preferred term.

  • Table 4

    Best overall response

    Best response*TN ≥65 y (n = 31)R/R (n = 101)R/R del(17p) (n = 34)All patients (N = 132)
    ORR (CR+PR+PR-L)26 (84)91 (90)27 (79)117 (89)
     CR7 (23)7 (7)2 (6)14 (11)
     PR17 (55)81 (80)22 (65)98 (74)
     PR-L2 (6)3 (3)3 (9)5 (4)
    SD3 (10)4 (4)4 (12)7 (5)
    PD02 (2)1 (3)2 (2)
    Missing2 (6)4 (4)2 (6)6 (5)
    • Values are n (%).

    • * By investigator assessment. NE, not evaluable; PD, progressive disease; SD, stable disease.